Rajoli RKR, Demkovich ZR, Flexner C, Owen A, Siccardi M. Predicting pharmacokinetics of a tenofovir alafenamide subcutaneous implant using PBPK modelling. Antimicrob Agents Chemother. 2020 May 18:AAC.00155-20. doi: 10.1128/AAC.00155-20. PMID: 32423957.
Background and Objectives: Long-acting (LA) administration using a subcutaneous (SC) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological (PK) profile and overcome sub-optimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV pre-exposure prophylaxis (PrEP). Daily drug-release requirements were then ascertained by averaging across the dosing interval.
Methods: A TAF PBPK model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of observed mean. TAF SC implants were simulated in five hundred individuals reporting predicted TAF plasma, tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells, cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above target concentration of 48 fmol/106 cells for a month was identified.
Results: TAF, TFV and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in PBMCs. TFV-DP cervical and rectal tissue concentration were predicted to be between 1.5 - 2.0 fmol/106 cells and 0.9 – 1.1 fmol/106 cells respectively for release rates between 1.3 – 1.6 mg/day.
Discussion: These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protections levels for approximately 6-months to 1 year. This modelling may inform future design of SC implants to mitigate adherence-issues for effective PrEP applications.